Wednesday, March 12, 2008

For those of you that have made it this far in the blog, here is a fairly detailed summary of Rasmussen's Encephalitis by Dr. Vining at John's Hopkins. Jessie's Neurologist in Baltimore. Anyway, if you are not into the details, skip this blog entry. This is a couple of levels higher than the super detailed medical papers, and a couple of levels deeper than most of what you read in the news journals. It is a very well written paper for the non-medical, but curious mind. Thanks Dr. Vining.

Rasmussen’s syndrome has remained an enigma since itwas first described as a clinical and pathological entity in 1958.Determining the etiology and how best to treat the conditionhas been an enduring struggle for clinicians, pathologists, surgeons,neuroscientists, and above all, for the families who needto make treatment decisions for their children. Bien and colleaguescapture the tension of this struggle in an excellent, recentlypublished review that provides the basis for the Europeanconsensus statement (1).Frustration with understanding Rasmussen’s syndrome beginswith efforts to determine the cause of this devastating disorder,which can destroy a cerebral hemisphere in previously normalchildren. When the pathologic findings were first noted(lymphocytic infiltration and microglial nodules), it was assumedthat a viral etiology would shortly be discovered. This lineof investigation was avidly pursued, with increasingly sophisticatedmethodology, until about a decade ago. No consistentlyreliable viral cause has been found. The next wave of enthusiasmin determining the etiology focused on the report of elevatedGluR3 antibodies (2) in some patients with Rasmussen’s syndromeand improvements that were seen when patients underwentplasmapheresis (3). Theories were postulated to explainhow these circulating antibodies were responsible for unihemisphericabnormalities. For example, one hypothesis suggestedthat a localized dysfunction (e.g., trauma, infection, etc.) ledto a breakdown of the blood–brain barrier, which then allowedthe GluR3 antibodies to attack neurons—either through cytotoxicactivation of the glutamate receptor or through complementactivation. However, elevated GluR3 antibodies havebeen found in other types of seizure disorders, and certainly theyare not found in all patients with Rasmussen’s syndrome. Interestcontinues in pursuing other humoral-related mechanisms,but in the last decade, the focus of much research has shiftedto examining the role of T-cell–mediated toxicity. This line ofinvestigation is fueled by the recognition that the vast majorityof inflammatory cells involved in Rasmussen’s syndrome are Tcells; in fact, they are cytotoxic CD8+ lymphocytes, which havebeen shown to attack neurons.The pathologic findings underscore the problems associatedwith understanding the cause of Rasmussen’s syndrome.Abnormal and normal tissue can be found in juxtaposition toeach other. What is the pathogenesis that can cause regions ofmultifocal destruction to be surrounded by normal appearingtissue? This feature of Rasmussen’s syndrome leads to a senseof futility for performing brain biopsies, and it also forces considerationof mechanisms postulated for multiple sclerosis andpostinfectiousencephalomyelitis (4).The clinical manifestations of Rasmussen’s syndrome areoften confusing. Although the hallmark of the disease is epilepsiapartialis continua, it does not occur in all patients and thenature of the focal seizures is very unusual. While the progressionof partial seizures is usually envisioned as a Jacksonianmarch, this image is routinely not the case in Rasmussen’s syndrome.Clonic activity may begin in the face; then in the hand,then the leg, and then the shoulder—the progression obviouslyreflects the patchy nature of the hemispheric pathology. Childrenalso can manifest features of a movement disorder beforeseizures are clearly apparent. The EEG often is confusing. Itmay show a paucity of epileptiform activity, even with epilepsiapartialis continua. Bilateral abnormalities are not uncommon.MRI has become one of the most important tools to confirm thepresence of Rasmussen’s syndrome. Atrophy, particularly progressiveatrophy, will appear. This feature, too, does not alwaysreflect the clinical situation. Extensive atrophy has been notedat clinical onset in some children while other children showminimal change for varying periods of time. Clinical and MRIprogression of the disease is quite variable. Disease progressioncan happen quickly with devastating results, and it can happeninsidiously, with periods of respite that circumvent more definitivetreatments. The European consensus group devotes a longtable to elaborating the differential diagnosis of Rasmussen’ssyndrome; however, close inspection of the list reveals that thecritical aspects of diagnosis are the history, EEG, and MRI (1).There is no test that is specific for Rasmussen’s syndrome, evenbiopsy.Medical treatment of Rasmussen’s syndrome has largelybeen a failure. Standard anticonvulsant therapy does not stopCurrent Review in Clinical Science 21the seizures. There has been more than a decade of experiencein using various forms of immunotherapy, but these are unsatisfactoryas well. Corticosteroids are probably effective in theshort-term and when status epilepticus is present. Long-termuse is problematic. Intravenous immunoglobulin replacementtherapy may stabilize patients for varying periods of time andhas been used in combination with steroids for some individuals.Side effects, including aseptic meningitis and phlebitis, exist,and the cost of treatment is not inconsequential. Plasmapheresiswas popular when GluR3 antibodies were believed to be theetiologic factor but does not appear to be effective for long-termuse.Newer forms of immunomodulation are hopeful, includingone described in an earlier report by Bienetal. (5) on the use oftacrolimus to stabilize neurological function and prevent furtheratrophy (without improved seizure control). In addition, preliminarywork using immunoablation with cyclophosphamideto eliminate the T-cell population that apparently is activatedand then destroying brain seems promising (6). Following cyclophosphamidetreatment, the lymphocytes that subsequentlyare generated presumably are na¨ıve and would not continue thedestruction of brain.Surgery also has been part of the artillery used to battleRasmussen’s syndrome. In the earliest days it became clear thatthe entire hemisphere had to be removed to produce a cure.However, in the 1960s and early 1970s, there was virtually amoratorium on using surgery because of concerns about longtermproblems, such as hemosiderosis. The moratorium endedwhen better techniques, as well as neuroimaging, became availablein the late 1970s and early 1980s. Surgeons continue tosearch to define the best technique, with variations that includehemidecorticectomy and hemispherotomy with disconnection.Proposed diagnostic criteria are at the heart of the consensusstatement paper by Bienetal., and they convey a sensitivityto properly diagnosing patients before extensive tissuedestruction has occurred (1). Early diagnosis is important toavoid the only cure currently available—removal of the hemisphere.If caught early, before the process destroys much of thehemisphere, the child might have seizures that could be controlledwith medication, without the significant handicap of ahemiplegia. Although previous attempts to establish diagnosticcriteria have failed, the consensus reached by the Europeangroup is significant. According to their statement, diagnosis isachieved in one of two ways (1). First, a diagnosis is reliablymade when all three criteria found in Part A of the consensusstatement are fulfilled: (i) focal seizures with unilateral corticaldeficit; (ii) EEG showing unihemispheric slowing (± epileptiformactivity), with unilateral seizure onset; and (iii) MRI,with unihemispheric focal cortical atrophy and either grey orwhite matter T2/FLAIR hyperintense signal or by changes inthe ipsilateralcaudate head. Second, diagnosis is attained if twoout of three of the features in Part B are fulfilled: (i) epilepsiapartialis continua or progressive unilateral cortical deficit, (ii)progressive unihemispheric focal cortical atrophy on MRI, or(iii) appropriate histopathology on biopsy. Using these criteria,the majority of individuals can be diagnosed without biopsy.The ultimate frustration in coping with Rasmussen’s syndromelies in the failure to be able to effectively treat thisobviously immune-mediated disease. The European consensusgroup has provided a thoughtful algorithm for the therapeuticapproach to patients with Rasmussen’s syndrome (1). Thealgorithm appropriately considers the seizures as well as the progressiveneurologic decline that accompanies the disease—bothof which clearly should influence decisions regarding therapy.Although the authors describe patients with ongoing progressionof neurologic dysfunction, who do not have intractableseizures and can be referred for continuing immunotherapy,this scenario is virtually unknown. The consensus group alsoprovided a list of recommended areas for future therapeuticresearch, which is admirable. The group recognizes the difficultiesin studying this population, particularly in regard to efficacyparameters.A few final thoughts about the struggle: parents and patientsengage in a particularly difficult process, as the affectedchildren were normal before this insidious process began. Parentsare looking for a cure that will halt the progression andreturn their child to previous functional levels. Anticonvulsantsand hemispherectomy cannot achieve this result. And so far, immunotherapyhas not been effective. Early diagnosis is critical—before significant neurological deterioration and destruction ofthe brain occurs. And finally, greater understanding of the etiologyof Rasmussen’s syndrome is essential to the ability todetermine specific therapies.http://jessiekelley.blogspot.com/

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About Me

Jessie is 8 years-old and in 2nd Grade. She has 3 brothers, Matt(12), Jake(10) and Josh(10). She loves people, and never met a stranger. She loves to laugh and sing and play. Jessie was diagnosed with Rasmussen's Encephalitis(RE), which is a rare brain disease that usually attacks healthy children about her age. The only known treatment for this cruel disease is a hemispherectomy (surgical removal of one-half of the brain)
This is an account of Jessie's confrontation with RE and her families attempts to navigate through a new world to bring her the best care possible. Surgery was on June 11, 2008.
This Blog is an attempt to help people undertand this disease and surgery, and to help others with kids going through it to find comfort and resource from someone who has been there before.
Read from bottom, up. It will be updated continuously through Jessie's Miraculous Recovery.
**To add Comments, just click "Comments".Or, email Jessie at Jessie@Hallzoo.com.